Abnormalities of the cardiac excitation process that result in cardiac arrhythmias continue to be a major cause of death and disability. In spite of important recent advances in understanding this process (notably, at the molecular level of membrane ion-channels), the mechanisms that underlie arrhythmogenic activity remain incompletely understood. Consequently, treatment (by drugs or non-pharmacological interventions) remains largely empirical with unpredictable outcome in many cases. The overall objective of this project is to further our understanding of mechanisms that underlie cardiac excitation and arrhythmias, and of principles behind interventions that lead to arrhythmia termination and prevention. It is our premise that understanding of mechanisms is imperative to the development of better treatment of arrhythmia and prevention of sudden death. As in the previous period of support, our approach is to study these phenomena through the use of theoretical, computer models in close conjunction with experimental observations. Specific aims are: (1) To continue the development of a model of the cardiac ventricular action potential based on kinetic description of single ion channels. (2) To characterize, using this model, the cellular electrophysiologic consequences of channel-function alteration caused by gene mutations and by abnormal calcium cycling. (3) To study the cellular electrophysiologic changes and single-cell arrhythmogenic behavior caused by ion-channel remodeling during myocardial infarction (MI). (4) To integrate the single cell behavior from (2) and (3) above into a multicellular model of cardiac tissue, and to study the mechanisms of arrhythmias associated with ion-channel mutation and with MI remodeling in the heterogeneous and anisotropic myocardium.